Synthesis
A. Synthesis of ethyl 2,4-difluorobenzoate. Hydrogen chloride gas (HCl(g)) was passed into a solution of ethanol (250 mL) containing 2,4-difluorobenzoic acid (36.0 g, 228 mmol) for 15 minutes. The reaction mixture was heated to 80 °C and stirred continuously for 24 hours. Upon completion of the reaction, the solution was partially concentrated and diluted with deionized water (300 mL). The aqueous layer was extracted using ethyl acetate (3 x 300 mL). The organic layers were combined, dried with anhydrous magnesium sulfate (MgSO4), filtered and concentrated to give 27.2 g (76% yield) of ethyl 2,4-difluorobenzoate as a clear oil. Mass spectrum (ESI): the exact calculated mass of C9H8F2O2 was 186.05; measured value: 186.05. The corresponding m/z peak was not observed. 1H NMR (400MHz, CDCl3): δ 8.01-7.95 (m, 1H), 6.95-6.85 (m, 2H), 4.39 (q, J = 7.1Hz, 2H), 1.39 (t, J = 7.1Hz, 3H).
References
[1] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 4, p. 1047 - 1049
[2] Patent: US2006/223810, 2006, A1. Location in patent: Page/Page column 23
[3] Patent: WO2006/21448, 2006, A1. Location in patent: Page/Page column 59
[4] Patent: US2010/324030, 2010, A1. Location in patent: Page/Page column 11
[5] Patent: CN108218848, 2018, A. Location in patent: Paragraph 0167-0169
